The SOAR of STIM1 interacts with plasma membrane lipids to form ER-PM contact sites

Depletion of Ca2+ from the endoplasmic reticulum (ER) causes the ER Ca2+ sensor STIM1 to form membrane contact sites (MCSs) with the plasma membrane (PM). At the ER-PM MCS, STIM1 binds to Orai channels to induce cellular Ca2+ entry. The prevailing view of this sequential process is that STIM1 interacts with the PM and with Orai1 using two separate modules: a C-terminal polybasic domain (PBD) for the interaction with PM phosphoinositides and the STIM-Orai activation region (SOAR) for the interaction with Orai channels. Here, using electron and fluorescence microscopy and protein-lipid interaction assays, we show that oligomeriza-tion of the SOAR promotes direct interaction with PM phosphoinositides to trap STIM1 at ER-PM MCSs. The interaction depends on a cluster of conserved lysine residues within the SOAR and is co-regulated by the STIM1 coil-coiled 1 and inactivation domains. Collectively, our findings uncover a molecular mechanism for formation and regulation of ER-PM MCSs by STIM1.

Automated summary

Depletion of Ca2+ from the endoplasmic reticulum (ER) leads to the formation of ER-PM membrane contact sites (MCSs) by the ER Ca2+ sensor STIM1. STIM1 binds to Orai channels at the ER-PM MCS, resulting in cellular Ca2+ entry. Previous studies suggested that STIM1 interacts with the plasma membrane (PM) and Orai1 using separate modules, but this study reveals that the oligomerization of the STIM-Orai activation region (SOAR) promotes direct interaction with PM phosphoinositides to trap STIM1 at ER-PM MCSs. This molecular mechanism is co-regulated by the STIM1 coil-coiled 1 and inactivation domains.